The long-term goal is to gain a better understanding of the biological roles of gamma (immune) interferon (IFN-gamma) and of a functionally related class of cytotoxic proteins, termed """"""""cytotoxins"""""""". Cytotoxins include lymphotoxin (LT), monocyte/macrophage-derived cytotoxin(s) (MCT) and tumor necrosis factor. Our broad working hypothesis is that IFN-gamma and cytotoxins mutually amplify their actions and that this synergism is important in inhibiting tumor cell growth and in limiting the spread of viruses and other intracellular infectious agents. The first specific aim is to gain a better understanding of the nature, multitude and mutual relationships of the various cytotoxin proteins produced by human lymphocytes and monocytes/macrophages. To answer these questions we shall perfect the methods of production of lymphocyte-derived LT and monocyte/macrophage-derived MCT from human cells, complete the purification of these proteins and produce specific polyclonal and monoclonal antibodies against them. The second specific aim is to elucidate the mechanism by which IFN-gamma produces enhanced monocyte cytotoxicity for tumor cells and to determine the possible role of cytotoxins in this process. This part of the project is based mainly on the recently established fact that IFN-gamma is uniquely active as a modulator of monocyte/macrophage functions, including activation of monocytes for tumor cell cytotoxicity. The third specific aim is to advance our understanding of the mechanisms of action of LT and MCT and of their synergism with IFN-gamma. The study of these questions will rely mainly on the analysis of the role of cellular receptors for cytotoxins and IFN-gamma and of the fate of cytotoxins and IFN-gamma after their binding to target cells. The proposed studies are likely to provide biologically relevant and medically significant information on host defenses in malignancies and virus infections.
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